2,4-disubstituted triazine derivatives

ABSTRACT

This invention concerns the use of the compounds of formula                  
 
the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein -a 1 =a 2 -a 3 =a 4 - forms a phenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl with the attached vinyl group; n is 0 to 4; and where possible 5; R 1  is hydrogen, aryl, formyl, C 1-6 alkylcarbonyl, C 1-6 alkyl, C 1-6 alkyloxycarbonyl or substituted C 1-6 alkyl; each R 2  independently is hydroxy, halo, optionally substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-6 alkyloxy, C 1-6 alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C 1-6 alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O) p R 4 , —NH—S(═O) p R 4 , —C(═O)R 4 , —NHC(═O)H, —C(═O)NHNH 2 , —NHC(═O)R 4 , —C(═NH)R 4  or a 5-membered heterocyclic ring; p is 1 or 2; L is optionally substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-7 cycloalkyl; or L is —X—R 3  wherein R 3  is optionally substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; X is —NR 1 —, —NH—NH—, —N═N—, —O—, —C(=O)—, —CHOH—, —S—, —S(═O)— or —S(═O) 2 —; aryl is optionally substituted phenyl; for the manufacture of a medicine for the treatment of subjects suffering from HIV (Human Immunodeficiency Virus) infection.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 09/831,808,filed Aug. 2, 2001, now U.S. Pat. No. 6,638,932, which is a NationalStage application under 35 U.S.C. § 371 of PCT/EP99/08688 filed Nov. 4,1999, which claims priority under 35 U.S.C. § 119 from EP 99203128.6,filed Sep. 24, 1999, which claims priority to provisional applicationSer. No. 60/107,799, filed Nov. 10, 1998.

The present invention is concerned with 2,4-disubstituted triazinederivatives having HIV replication inhibiting properties. The inventionfurther relates to methods for their preparation and pharmaceuticalcompositions comprising them. The invention also relates to the use ofsaid compounds in the manufacture of a medicament useful for thetreatment of subjects suffering from HIV (Human Immunodeficiency Virus)infection.

EP-0,834,507 discloses substituted diamino 1,3,5-triazine derivativeshaving HIV replication inhibiting properties. The present compoundsdiffer from the known 1,3,5-triazines by structure and by their improvedHIV replication inhibiting properties.

The present invention concerns the use of the compounds of formula

the N-oxides, pharmaceutically acceptable addition salts, quaternaryamines and stereochemically isomeric forms thereof, wherein

-   -a¹=a²-a³=a⁴- represents a bivalent radical of formula

—CH═CH—CH═CH— (a-1); —N═CH—CH═CH— (a-2); —N═CH—N═CH— (a-3); —N═CH—CH═N—(a-4); —N═N—CH═CH— (a-5);

-   n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n may    also be 5;-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; and-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁴,    —NH—S(═O)_(p)R⁴, —C(═O)R⁴, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁴,    —C(═NH)R⁴ or a radical of formula    wherein each A independently is N, CH or CR⁴;    -   B is NH, O, S or NR⁴;    -   p is 1 or 2; and    -   R⁴ is methyl, amino, mono- or dimethylamino or polyhalomethyl;-   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said aliphatic group may be substituted with one or two    substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or-   L is —X—R³ wherein    -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; and    -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—        or —S(═O)₂—; aryl is phenyl or phenyl substituted with one, two,        three, four or five substituents each independently selected        from halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano,        nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy;        for the manufacture of a medicine for the treatment of subjects        suffering from HIV (Human Immunodeficiency Virus) infection.

This invention also concerns compounds of formula (I′) which are definedas compounds of formula (I) wherein the compounds cited in the followingreferences

-   -   Recl. Trav. Chim. Pays-Bas (1969), 88 (4), 426–38.    -   Polym. J. (Tokyo) (1996), 28 (4), 337–42.    -   J. Inst. Chem. (India) (1978), 50 (5), 213–14.    -   Nippon Kagaku Kaishi (1977), Issue 4, 549–55.    -   Kobunshi Kagaku (1973), 30 (12), 720–6.    -   SU 189438    -   DE 2226474        are excluded;        i.e. compounds of formula        the N-oxides, addition salts, quaternary amines and        stereochemically isomeric forms thereof, wherein the        substituents are as defined under formula (I); with the proviso        that compounds wherein    -   L is C₁₋₃alkyl; R¹ is selected from hydrogen, ethyl and methyl;        -a¹=a²-a³=a⁴- represents a bivalent radical of formula (a-1); n        is 0 or 1 and R² is selected from fluoro, chloro, methyl,        trifluoromethyl, ethyloxy and nitro; or    -   L is —X—R³, X is —NH—; R¹ is hydrogen; -a¹=a²-a³=a⁴- represents        a bivalent radical of formula (a-1); n is 0 or 1 and R² is        selected from chloro, methyl, methyloxy, cyano, amino and nitro        and R³ is phenyl, optionally substituted with one substituent        selected from chloro, methyl, methyloxy, cyano, amino and nitro;        and the compounds    -   N,N′-dipyridinyl-(1,3,5)-triazine-2,4-diamine;    -   (4-chloro-phenyl)-(4(1-(4-isobutyl-phenyl)-ethyl)-(1,3,5)        triazin-2-yl)-amine are not included.

A special group of compounds are compounds of formula (I′), theN-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms thereof, wherein -a¹=a²-a³=a⁴- represents a bivalentradical of formula

—CH═CH—CH═CH— (a-1); —N═CH—CH═CH— (a-2); —N═CH—N═CH— (a-3); —N═CH—CH═N—(a-4); —N═N—CH═CH— (a-5);n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³=a⁴- is (a-1), then n mayalso be 5;

-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; and-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁴,    —NH—S(═O)_(p)R⁴, —C(═O)R⁴, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁴,    —C(═NH)R⁴ or a radical of formula    wherein each A independently is N, CH or CR⁴;    -   B is NH, O, S or NR⁴;    -   p is 1 or 2; and    -   R⁴ is methyl, amino, mono- or dimethylamino or polyhalomethyl;-   L is C₄₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said aliphatic group may be substituted with one or two    substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or-   L is —X—R³ wherein    -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with two, three, four or five substituents each        independently selected from the substituents defined in R²; and    -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—        or —S(═O)₂—;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;-   and suitably N,N′-dipyridinyl-(1,3,5)-triazine-2,4-diamine is    excluded.

Another special group of compounds are those compounds having theformula

the N-oxides, addition salts, quaternary amines and stereochemicallyisomeric forms thereof, wherein

-   -b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula

—CH═CH—C(R^(2a))═CH—CH═ (b-1); —N═CH—C(R^(2a))═CH—CH═ (b-2);—CH═N—C(R^(2a))═CH—CH═ (b-3); —N═CH—C(R^(2a))═N—CH═ (b-4);—N═CH—C(R^(2a))═CH—N═ (b-5); —CH═N—C(R^(2a))═N—CH═ (b-6);—N═N—C(R^(2a))═CH—CH═ (b-7);

-   q is 0, 1, 2; or where possible q is 3 or 4;-   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,    C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,    C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl;-   R^(2a) is cyano; aminocarbonyl; mono- or di(methyl)aminocarbonyl;    C₁₋₆alkyl substituted with cyano, aminocarbonyl or mono- or    di(methyl)aminocarbonyl; C₂₋₆alkenyl substituted with cyano; or    C₂₋₆alkynyl substituted with cyano;-   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally    substituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyl    optionally substituted with one or more halogen atoms or cyano,    C₂₋₆alkynyl optionally substituted with one or more halogen atoms or    cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,    amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,    polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁴,    —NH—S(═O)_(p)R⁴, —C(═O)R⁴, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁴,    —C(═NH)R⁴ or a radical of formula    wherein each A independently is N, CH or CR⁴;    -   B is NH, O, S or NR⁴;    -   p is 1 or 2; and    -   R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;-   L is C₄₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby    each of said aliphatic group may be substituted with one of two    substituents independently selected from    -   C₃₋₇cycloalkyl,    -   indolyl or isoindolyl, each optionally substituted with one,        two, three or four substituents each independently selected from        halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,        nitro, amino, polyhalomethyl, polyhalomethyloxy and        C₁₋₆alkylcarbonyl,    -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with one, two, three, four or five substituents each        independently selected from the substituents defined in R²; or-   L is —X—R³ wherein    -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,        wherein each of said aromatic rings may optionally be        substituted with two, three, four or five substituents each        independently selected from the substituents defined in R²; and    -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—        or —S(═O)₂—;-   aryl is phenyl or phenyl substituted with one, two, three, four or    five substituents each independently selected from halo, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and    polyhaloC₁₋₆alkyloxy;-   and suitably N,N′-dipyridinyl-(1,3,5)-triazine-2,4-diamine is    excluded.

Said special groups of compounds are deemed novel and can be used as amedicine.

The present invention also relates to a method of treating warm-bloodedanimals suffering from HIV (Human Immunodeficiency Virus) infection.Said method comprises the administration of a therapeutically effectiveamount of a compound of formula (I), (I′) or (I-a) or a N-oxide form, apharmaceutically acceptable addition salt, a quaternary amine or astereochemically isomeric form thereof in admixture with apharmaceutical carrier.

As used in the foregoing definitions and hereinafter C₁₋₃alkyl as agroup or part of a group encompasses the straight and branched chainsaturated hydrocarbon radicals having from 1 to 3 carbon atoms such as,methyl, ethyl and propyl; C₁₋₄alkyl encompasses the straight andbranched chain saturated hydrocarbon radicals as defined in C₁₋₃alkyl aswell as butyl; C₁₋₆alkyl encompasses the straight and branched chainsaturated hydrocarbon radicals as defined in C₁₋₄alkyl as well as thehigher homologues thereof containing 5 to 6 carbon atoms such as pentyl,hexyl, 2-methylbutyl and the like; C₁₋₁₀alkyl encompasses the straightand branched chain saturated hydrocarbon radicals as defined inC₁₋₆alkyl as well as the higher homologues thereof containing 7 to 10carbon atoms such as, heptyl, octyl, nonyl or decyl; C₄₋₁₀alkylencompasses the straight and branched chain saturated hydrocarbonradicals as defined above, having from 4 to 10 carbon atoms;C₃₋₇cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl; C₂₋₆alkenyl defines straight and branchedchain hydrocarbon radicals containing one double bond and having from 2to 6 carbon atoms such as, 2-ethenyl, 2-propenyl, 2-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl and the like; C₂₋₁₀alkenylencompasses the straight and branched chain hydrocarbon radicals asdefined in C₂₋₆alkenyl as well as the higher homologues thereofcontaining 7 to 10 carbon atoms such as 3-heptenyl, 2-octenyl,2-nonenyl, 2-decenyl and the like, whereby the carbon atom attached tothe triazine ring is preferably an aliphatic carbon atom; C₂₋₆alkynyldefines straight and branched chain hydrocarbon radicals containing onetriple bond and having from 2 to 6 carbon atoms such as, 2-ethynyl,2-propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl,3-hexynyl and the like; C₂₋₁₀alkynyl encompasses the straight andbranched chain hydrocarbon radicals as defined in C₂₋₆alkynyl as well asthe higher homologues thereof containing 7 to 10 carbon atoms such as3-heptynyl, 2-octynyl, 2-nonynyl, 2-decynyl and the like, whereby thecarbon atom attached to the triazine ring is preferably an aliphaticcarbon atom. The term C₁₋₆alkyloxy defines straight or branched chainsaturated hydrocarbon radicals such as methoxy, ethoxy, propyloxy,butyloxy, pentyloxy, hexyloxy, 1-methylethyloxy, 2-methylpropyloxy,2-methylbutyloxy and the like; C₃₋₆cycloalkyloxy is generic tocyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

As used herein before, the term (═O) forms a carbonyl moiety whenattached to a carbon atom, a sulfoxide group when attached once to asulfur atom, and a sulfonyl group when attached twice to a sulfur atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used inthe foregoing and hereinafter, polyhalomethyl as a group or part of agroup is defined as mono- or polyhalosubstituted methyl, in particularmethyl with one or more fluoro atoms, for example, difluoromethyl ortrifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group isdefined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, thegroups defined in halomethyl, 1,1-difluoro-ethyl and the like. In casemore than one halogen atoms are attached to an alkyl group within thedefinition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the sameor different.

For therapeutic use, salts of the compounds of formula (I), (I′) or(I-a) are those wherein the counterion is pharmaceutically acceptable.However, salts of acids and bases which are not pharmaceuticallyacceptable may also find use, for example, in the preparation orpurification of a pharmaceutically acceptable compound. All salts,whether pharmaceutically acceptable or not are included within the ambitof the present invention.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to comprise the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I), (I′) or (I-a) are able toform. The compounds of formula (I), (I′) or (I-a) which have basicproperties can be converted in their pharmaceutically acceptable acidaddition salts by treating said base form with an appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric;nitric; phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic,malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic,tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic,p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and thelike acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I), (I′) or (I-a) containing an acidic protonmay also be converted into their non-toxic metal or amine addition saltforms by treatment with appropriate organic and inorganic bases.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The term addition salts also comprises the hydrates and the solventaddition forms which the compounds of formula (I), (I′) or (I-a) areable to form. Examples of such forms are e.g. hydrates, alcoholates andthe like.

It will be appreciated that some of the compounds of formula (I), (′) or(I-a) and their N-oxides, addition salts, quaternary amines andstereochemically isomeric forms may contain one or more centers ofchirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible stereoisomeric forms which the compounds of formula(I), (I′) or (I-a) and their N-oxides, addition salts, quaternary aminesor physiologically functional derivatives may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically isomeric forms, saidmixtures containing all diastereomers and enantiomers of the basicmolecular structure as well as each of the individual isomeric forms offormula (I), (I′) or (I-a) and their N-oxides, addition salts orquaternary amines substantially free, i.e. associated with less than10%, preferably less than 5%, in particular less than 2% and mostpreferably less than 1% of the other isomers. In particular, stereogeniccenters may have the R- or S-configuration; substituents on bivalentcyclic (partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an E-or Z-stereochemistry at said double bond. Stereochemically isomericforms of the compounds of formula (I), (I′) or (I-a) are obviouslyintended to be embraced within the scope of this invention.

Some of the compounds of formula (I), (I′) or (I-a) may also exist intheir tautomeric forms. Such forms although not explicitly indicated inthe above formula are intended to be included within the scope of thepresent invention.

Lines drawn into ring systems from substituents indicate that the bondmay be attached to any of the suitable ring atoms.

When any variable (e.g. R²) occurs more than one time in anyconstituent, each definition is independent.

Whenever used hereinafter, the term “compounds of formula (I)”,“compounds of formula (I′)”, or “compounds of formula (I-a)” is meant toinclude also the N-oxides, the addition salts, the quaternary amines andall stereoisomeric forms.

An interesting group of compounds are those compounds of formula (I) or(I′) wherein one or more of the following conditions are met:

-   (i) n is 1;-   (ii) -a¹=a²-a³=a⁴- represents a bivalent radical of formula (a-1);-   (iii) R¹ is hydrogen or alkyl;-   (iv) R² is cyano; aminocarbonyl; mono- or di(methyl)aminocarbonyl;    C₁₋₄alkyl substituted with cyano, aminocarbonyl or mono- or    di(methyl)aminocarbonyl; and more in particular, R² is on the 4    position relative to the —NR¹— moiety;-   i) L is —X—R³ wherein X is preferably —NR¹—, —O— or —S—, most    preferably X is —NH—, and R³ is substituted phenyl with C₁₋₆alkyl,    halogen and cyano as preferred substituents.

Another interesting group of compounds contains those compounds offormula (I-a) wherein one or more of the following restrictions apply:

-   i) -b¹=b²-C(R^(2a))=b³-b⁴=is a radical of formula (b-1);-   ii) q is 0;-   iii) R^(2a) is cyano; aminocarbonyl; mono- or    di(methyl)aminocarbonyl; C₁₋₆alkyl substituted with cyano,    aminocarbonyl or mono- or di(methyl)aminocarbonyl, preferably R^(2a)    is cyano;-   iv) L is —X—R³ wherein X is preferably —NR¹—, —O— or —S—, most    preferably X is —NH—, and R³ is substituted phenyl with C₁₋₆alkyl,    halogen and cyano as preferred substituents.

Preferred compounds are those compounds of formula (I′) or (I-a) whereinL is —X—R³ wherein R³ is a disubstituted phenyl group or atrisubstituted phenyl group, each substituent independently selectedfrom chloro, bromo, fluoro, cyano or C₁₋₄alkyl.

Compounds of formula (I′) wherein L is a radical of formula —X—R³, saidcompounds are represented by formula (I′-a), can be prepared by reactingan intermediate of formula (II) wherein W¹ is a suitable leaving group,for example, a halogen, with an amine derivative of formula (III) in areaction-inert solvent, for example, tetrahydro-furan, 1,4-dioxane orthe like, in the presence of a suitable base such as, triethylamine; andsubsequently reacting the thus obtained intermediate of formula (IV)with an intermediate of formula (V) in a reaction-inert solvent such asacetonitrile, 1,4-dioxane or the like, in the presence of a base such aspotassium carbonate, sodium hydride, N,N-diisopropyl-ethylamine or thelike.

The order of the above reaction scheme may also be reversed, i.e. firstan intermediate of formula (II) may be reacted with an intermediate offormula (V), and then, the resulting intermediate may further be reactedwith an amine derivative of formula (III); thus forming a compound offormula (I′-a).

The reaction products may be isolated from the reaction medium and, ifnecessary, further purified according to methodologies generally knownin the art such as, extraction, crystallization, distillation,trituration and chromatography.

Compounds of formula (I′) wherein L is an optionally substitutedC₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, said L beingrepresented by L_(a) and said compounds being represented by formula(I′-b), can be prepared by first making a Grignard reagent of anintermediate of formula (VI) wherein W² is a suitable leaving group suchas, a halogen, e.g. bromine, in the presence of magnesium in areaction-inert solvent such as, diethyl ether, and subsequently reactingsaid Grignard reagent with an intermediate of formula (VII) wherein W¹is a suitable leaving group such as, a halogen, e.g. chlorine, in areaction-inert solvent, for example, benzene, thus forming anintermediate of formula (VIII). It may be convenient to perform theabove reaction under an inert atmosphere, for instance, argon.Intermediate (VIII) may be isolated from its reaction medium, or may bein situ further reacted with an intermediate of formula (III) in areaction-inert solvent such as, 1,4-dioxane, and in the presence of asuitable base such as, diisopropylethylamine or the like, thus forming acompound of formula (I′-b).

The compounds of formula (I′) may further be prepared by convertingcompounds of formula (I′) into each other according to art-known grouptransformation reactions.

The compounds of formula (I′) may be converted to the correspondingN-oxide forms following art-known procedures for converting a trivalentnitrogen into its N-oxide form. Said N-oxidation reaction may generallybe carried out by reacting the starting material of formula (I′) with anappropriate organic or inorganic peroxide. Appropriate inorganicperoxides comprise, for example, hydrogen peroxide, alkali metal orearth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide; appropriate organic peroxides may comprise peroxy acids suchas, for example, benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid,peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g.t.butyl hydro-peroxide. Suitable solvents are, for example, water, loweralcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.dichloromethane, and mixtures of such solvents.

Some of the intermediates as mentioned hereinabove are commerciallyavailable or can be prepared according to art-known procedures.

Compounds of formula (I′) and some of the intermediates may have one ormore stereogenic centers in their structure, present in a R or a Sconfiguration.

The compounds of formula (I′) as prepared in the hereinabove describedprocesses may be synthesized as a mixture of stereoisomeric forms, inparticular in the form of racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I′) may be converted into thecorresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I′)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy,amino and carboxylic acid. Suitable protecting groups for hydroxyinclude trialkylsilyl groups (e.g. tert-butyldimethylsilyl,tert-butyldiphenylsilyl or trimethylsilyl), benzyl andtetrahydropyranyl. Suitable protecting groups for amino includetert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groupsfor carboxylic acid include C₁₋₆alkyl or benzyl esters.

The protection and deprotection of functional groups may take placebefore or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups inOrganic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & PG M Wutz, Wiley Interscience (1991).

The compounds of formula (I), (I′) and (I-a) show antiretroviralproperties, in particular against Human Immunodeficiency Virus (HIV),which is the aetiological agent of Acquired Immune Deficiency Syndrome(AIDS) in humans. The HIV virus preferentially infects human T-4 cellsand destroys them or changes their normal function, particularly thecoordination of the immune system. As a result, an infected patient hasan everdecreasing number of T4 cells, which moreover behave abnormally.Hence, the immunological defense system is unable to combat infectionsand neoplasms and the HIV infected subject usually dies by opportunisticinfections such as pneumonia, or by cancers. Other conditions associatedwith HIV infection include thrombocytopaenia, Kaposi's sarcoma andinfection of the central nervous system characterized by progressivedemyelination, resulting in dementia and symptoms such as, progressivedysarthria, ataxia and disorientation. HIV infection further has alsobeen associated with peripheral neuropathy, progressive generalizedlymphadenopathy (PGL) and AIDS-related complex (ARC).

The present compounds also show activity against HIV-1 strains that haveacquired resistance to art-known non-nucleoside reverse transcriptaseinhibitors. They also have little or no binding affinity to human α-1acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I), (I′) or (I-a), their N-oxides, addition salts andstereochemically isomeric forms, are useful in the treatment ofindividuals infected by HIV and for the prophylaxis of these infections.In general, the compounds of the present invention may be useful in thetreatment of warm-blooded animals infected with viruses whose existenceis mediated by, or depends upon, the enzyme reverse transcriptase.Conditions which may be prevented or treated with the compounds of thepresent invention, especially conditions associated with HIV and otherpathogenic retroviruses, include AIDS, AIDS-related complex (ARC),progressive generalized lymphadenopathy (PGL), as well as chronic CNSdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

The compounds of the present invention or any subgroup thereof maytherefore be used as medicines against above-mentioned conditions. Saiduse as a medicine or method of treatment comprises the systemicadministration to HIV-infected subjects of an amount effective to combatthe conditions associated with HIV and other pathogenic retroviruses,especially HIV-1.

The compounds of the present invention or any subgroup thereof may beformulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs. Toprepare the pharmaceutical compositions of this invention, an effectiveamount of the particular compound, optionally in addition salt form, asthe active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin, diluents,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral unit dosage forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

Apart from their pharmacological properties, some of the compounds offormula (I′) have interesting physicochemical properties. For instance,they have good solubility. To aid solubility of the less solublecompounds of formula (I′), suitable ingredients, e.g. cyclodextrins, maybe included in the compositions. Appropriate cyclodextrins are α-, β-,γ-cyclodextrins or ethers and mixed ethers thereof wherein one or moreof the hydroxy groups of the anhydroglucose units of the cyclodextrinare substituted with C₁₋₆alkyl, particularly methyl, ethyl or isopropyl,e.g. randomly methylated β-CD; hydroxyC₁₋₆alkyl, particularlyhydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC₁₋₆alkyl,particularly carboxymethyl or carboxy-ethyl; C₁₋₆alkylcarbonyl,particularly acetyl. Especially noteworthy as complexants and/orsolubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD,2-hydroxyethyl-β-CD, 2-hydroxyethyl-γ-CD, 2-hydroxypropyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of theaverage number of moles of alkoxy units per mole of anhydroglucose. Theaverage substitution degree (D.S.) refers to the average number ofsubstituted hydroxyls per anhydroglucose unit. The M.S. and D.S. valuecan be determined by various analytical techniques such as nuclearmagnetic resonance (NMR), mass spectrometry (MS) and infraredspectroscopy (IR). Depending on the technique used, slightly differentvalues may be obtained for one given cyclodextrin derivative.Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration compriseparticles obtainable by melt-extruding a mixture comprising a compoundof formula (I′) and an appropriate water-soluble polymer andsubsequently milling said melt-extruded mixture. Said particles can thenbe formulated by conventional techniques into pharmaceutical dosageforms such as tablets and capsules.

Said particles consist of a solid dispersion comprising a compound offormula (I′) and one or more pharmaceutically acceptable water-solublepolymers. The preferred technique for preparing solid dispersions is themelt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I′) and an appropriate        water-soluble polymer,    -   b) optionally blending additives with the thus obtained mixture,    -   c) heating the thus obtained blend until one obtains a        homogenous melt,    -   d) forcing the thus obtained melt through one or more nozzles;        and    -   e) cooling the melt till it solidifies.

The solid dispersion product is milled or ground to particles having aparticle size of less than 600 μm, preferably less than 400 μm and mostpreferably less than 125 μm.

The water-soluble polymers in the particles are polymers that have anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700 mPa.s, andmost preferred of 1 to 100 mPa.s. For example, suitable water-solublepolymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, carboxyalkylcelluloses, alkali metal salts ofcarboxyalkylcelluloses, carboxyalkylalkylcelluloses,carboxyalkylcellulose esters, starches, pectines, chitin derivates,polysaccharides, polyacrylic acids and the salts thereof,polymethacrylic acids and the salts and esters thereof, methacrylatecopolymers, polyvinylalcohol, polyalkylene oxides and copolymers ofethylene oxide and propylene oxide. Preferred water-soluble polymers areEudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer inthe preparation of the above-mentioned particles as is disclosed in WO97/18839. Said cyclodextrins include the pharmaceutically acceptableunsubstituted and substituted cyclodextrins known in the art, moreparticularly α, β or γ cyclodextrins or the pharmaceutically acceptablederivatives thereof.

Substituted cyclodextrins which can be used include polyethers describedin U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are etherswherein the hydrogen of one or more cyclodextrin hydroxy groups isreplaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl orC₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particularsuch substituted cyclodextrins are ethers wherein the hydrogen of one ormore cyclodextrin hydroxy-groups is replaced by C₁₋₃alkyl,hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl,ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl orcarboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g.dimethyl-α-cyclodextrin as described in Drugs of the Future, Vol. 9, No.8, p. 577–578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropylβ-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such analkyl ether may be a methyl ether with a degree of substitution of about0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin mayfor example be formed from the reaction between β-cyclodextrin anpropylene oxide and may have a MS value of about 0.125 to 10, e.g. about0.3 to 3.

A more novel type of substituted cyclodextrins issulfobutylcyclodextrines.

The ratio of compound of formula (I′) over cyclodextrin may vary widely.For example ratios of 1/100 to 100/1 may be applied. Interesting ratiosof compound of formula (I′) over cyclodextrin range from about 1/10 to10/1. More interesting ratios range from about 1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I′)in the form of nanoparticles which have a surface modifier adsorbed onthe surface thereof in an amount sufficient to maintain an effectiveaverage particle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of thecompound of formula (I′) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

Yet another interesting way of formulating the compounds of formula (I′)involves a pharmaceutical composition whereby the compounds of formula(I′) are incorporated in hydrophilic polymers and applying this mixtureas a coat film over many small beads, thus yielding a composition whichcan conveniently be manufactured and which is suitable for preparingpharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating filmof a hydrophilic polymer and a compound of formula (I′) and aseal-coating polymer layer.

Materials suitable for use as cores in the beads are manifold, providedthat said materials are pharmaceutically acceptable and have appropriatedimensions and firmness. Examples of such materials are polymers,inorganic substances, organic substances, and saccharides andderivatives thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine theeffective daily amount from the test results presented here. In generalit is contemplated that an effective daily amount would be from 0.01mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I), (I′) or (I-a) used, the particularcondition being treated, the severity of the condition being treated,the age, weight and general physical condition of the particular patientas well as other medication the individual may be taking, as is wellknown to those skilled in the art. Furthermore, it is evident that saideffective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines and are not intended to limit the scope or use of theinvention to any extent.

Also, the combination of an antiretroviral compound and a compound offormula (I), (I′) or (I-a) can be used as a medicine. Thus, the presentinvention also relates to a product containing (a) a compound of formula(I), (I′), or (I-a) and (b) another antiretroviral compound, as acombined preparation for simultaneous, separate or sequential use inanti-HIV treatment. The different drugs may be combined in a singlepreparation together with pharmaceutically acceptable carriers. Saidother antiretroviral compounds may be known antiretroviral compoundssuch as nucleoside reverse transcriptase inhibitors, e.g. zidovudine(3′-azido-3′-deoxythymidine, AZT), didanosine (dideoxy inosine; ddI),zalcitabine (dideoxycytidine, ddC) or lamivudine(3′-thia-2′-3′-dideoxycytidine, 3TC) and the like; non-nucleosidereverse transciptase inhibitors such as suramine, pentamidine,thymopentin, castanospermine, efavirenz, dextran (dextran sulfate),foscarnet-sodium (trisodium phosphono formate), nevirapine(11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and thelike; compounds of the TIBO(tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepine-2 (1H)-one andthione)-type e.g.(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione; compounds of the α-APA (α-anilino phenyl acetamide) typee.g. α-[(2-nitrophenyl)amino]-2,6-dichlorobenzene-acetamide and thelike; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitorse.g. indinavir, ritanovir, saquinovir, ABT-378 and the like; orimmunomodulating agents, e.g. levamisole and the like. The compound offormula (I), (I′) or (I-a) can also be combined with another compound offormula (I), (I′) or (I-a).

The following examples are intended to illustrate the present invention.

Experimental Part

Hereinafter, the term ‘RT’ means room temperature, ‘THF’ meanstetrahydrofuran and ‘EtOAc’ means ethyl acetate.

A. Preparation of the Intermediates

EXAMPLE A.1

Starting material 2,4-dichloro-1,3,5-triazine was prepared in 34.8%yield by the method of Synthesis 1981, 907. A solution of2,4-dichloro-1,3,5-triazine (0.0238 mol) in 1,4-dioxane (120 ml) wasprepared with vigorous stirring. 4-Aminobenzonitrile (0.0240 mol) wasadded in one portion, resulting in a suspension. N,N-bis(1-methylethyl)ethanamine (0.0241 mol) was added. The reaction mixture was stirred atRT for 48 hours. The reaction was concentrated in vacuo to produce aviscous orange syrup which was dissolved with EtOAc and treated withcold 1 M NaOH. The combined aqueous phases were back extracted withEtOAc. The combined organic extracts were dried over MgSO₄, filtered andthe filtrate was evaporated to give 5.27 g of yellow powder that wassubjected to flash chromatography on silica gel (eluent: 100% CH₂Cl₂ to90:10 CH₂Cl₂/Et₂O). The pure fractions were collected and the solventwas evaporated to give 3.87 g of off white solid that was recrystallizedfrom CH₃CN, filtered off and dried, yielding 3.57 g (64.8%) of4-[(4-chloro-1,3,5-triazin-2-yl)amino]benzonitrile (Intermediate 1).

B. Preparation of the Final Compounds

EXAMPLE B.1

a) Intermediate (1) (0.00160 mol) was partially dissolved by stirring in1,4-dioxane (10 ml). Sequentially, 2,4,6-trimethylbenzenamine (0.00164mol) and N,N-bis(1-methylethyl)ethanamine (0.00164 mol) were added, andthe resulting suspension was heated to reflux with stirring. The mixturecleared at 40–50° C. After 4.5 days at reflux, the reaction was cooledto RT, diluted with Et₂O, and treated with cold 1 M NaOH. EtOAc wasadded to dissolve all of the material between the 2 layers. The organicphase was separated and extracted with cold 1 M NaOH. The combinedaqueous fractions were washed with EtOAc, adding solid NaOH to adjustthe pH to >10. The combined organic phases were dried (MgSO₄), filteredand the solvent was evaporated in vacuo to give 0.60 g brown waxy solid.This fraction was purified by flash column chromatography over silicagel (eluent: 100% CH₂Cl₂ to 80:20 CH₂Cl₂/Et₂O). The pure fractions werecollected and the solvent was evaporated to give 0.40 g of white waxysolid that was recrystallized from CH₃CN. The precipitate was filteredoff and dried, yielding 0.24 g (45.4%) of4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 1).

b) Intermediate (1) (0.00203 mol) and 1,4-dioxane (15 ml) were added toa flask equipped with a condenser. The mixture was stirred vigorously,and 2,6-dibromo-4-(1-methylethyl)benzenamine (0.00205 mol) andN-ethyl-N-(1-methylethyl)-2-propanamine (0.00207 mol) were sequentiallyadded. The reaction was heated to reflux for 5 days (TLC showed someprogress). Refluxing was maintained for another day (TLC showed furtherslow progress). After 12 days total, the reaction was a darker brownwith some dark precipitate. The reaction mixture was cooled to roomtemperature, diluted with EtOAc, treated with cold 1 M NaOH (2×) leavingsome brown insoluble solid at the interface. The aqueous phase was pHadjusted to >10 with solid NaOH and was backwashed with EtOAc (2×). Theorganic phases were combined, dried over MgSO₄, filtered andconcentrated in vacuo to obtain 0.99 g brown residue. Purification fromreverse phase prep HPLC and lyophilization yielded 0.020 g of4-[[4-[[2,6-dibromo-4-(1-methylethyl)phenyl]amino]-1,3,5-triazin-2-yl]amino]benzonitrile(2.0%, beige fluffy solid) mp. 245–247° C. (compound 8).

c) Intermediate (1) (0.00203 mol) and 1,4-dioxane (15 ml) were added toa flask equipped with a condenser. The mixture was stirred vigorously,and 2,6-dimethyl-4-(1,1-dimethylethyl)benzenamine (0.00203 mol) andN-ethyl-N-(1-methylethyl)-2-propanamine (0.00207 mol) were sequentiallyadded. The reaction was heated to reflux temperature for 5 days (TLCshowed high conversion). Refluxing was maintained for another day (TLCshowed no further progress). The reaction was cooled to roomtemperature, diluted with EtOAc, and treated with cold 1 M NaOH. Theaqueous phase was pH adjusted to >10 with solid NaOH and backwashed withEtOAc. The organic phases were combined and dried over MgSO₄.Concentration afforded 0.90 g tan foam. The residue was purified byflash column chromatography over silica gel (eluent: CH₂Cl₂ to 90:10CH₂Cl₂:Et₂O). The pure fractions were collected and the solvent wasevaporated to give 0.36 g white solid. This fraction was recrystallizedfrom CH₃CN, filtered off and dried. Yielding: 0.28 g of4-[[4-[[2,6-dimethyl-4-(1,1-dimethylethyl)-phenyl]amino]-1,3,5-triazin-2-yl]amino]benzonitrile(37.0%, white crystalline solid) (compound 9).

EXAMPLE B.2

a) NaH (0.0025 mol) and THF (5 ml) were added to a flask equipped withan addition funnel. A solution of 2,4,6-trimethylphenol (0.00206 mol) inTHF (15 ml) was added dropwise with stirring over 15 minutes. Thereaction mixture was stirred at room temperature for 45 minutes.Intermediate (1) (0.00203 mol) was added in one portion. The reactionmixture was stirred for 4 days. The reaction was quenched by pouringover ice (75 ml). Upon melting, a minimal amount of precipitate formed.The mixture was treated with Et₂O and EtOAc and the fractions wereseparated. The pH of the aqueous fraction was adjusted to >10 bytreatment with solid NaOH and extracted with EtOAc. The combined organicphases were treated with cold 1 M NaOH. The organic phases were driedover MgSO₄. Concentration in vacuo afforded 0.65 g white powder. Thisfraction was recrystallized from CH₃CN, filtered off and dried, yielding0.50 g (74.4%) of4-[[4-(2,4,6-trimethylphenoxy)-1,3,5-triazin-2-yl]amino]benzonitrile(compound 2). b) 1-Methyl-2-pyrrolidinone, (5 ml) was added to3,5-dimethyl-4-hydroxybenzonitrile (0.00258 mol) in a sealed tubereaction flask. The tube was capped with a septum and Ar was introducedvia a syringe needle. NaH 60% in oil (0.0030 mol) was added in oneportion, and the reaction was stirred for 30 min as the mixtureeffervesced and became an orange solution. A suspension of intermediate(1) (0.00173 mol) in 1,4-dioxane (15 ml) was added and the flask wassealed and then heated to 160–170° C. for 64 hours. The reaction mixturewas cooled to room temperature and analyzed by HPLC/MS which showed somedesired product formation with complete consumption of intermediate (1).The sample was poured into ice (±200 ml) and allowed to melt. Aprecipitate formed and the mixture was cooled in the refrigerator.Collected 0.31 g brown powder by suction filtration which was subjectedto purification through preparative HPLC. Upon lyophilization, obtained0.02 g of4-[[4-[(4-cyanophenyl)amino]-1,3,5-triazin-2-yl]oxy]-3,5-dimethylbenzonitrilebeige flaky solid (3.4%); mp. 248–250° C. (compound 11).

EXAMPLE B.3

Intermediate (1) (0.00203 mol) and 1,4-dioxane (15 ml) were added to aflask and stirred. Sequentially, 2,4,6-trimethylbenzenethiol (0.00204mol) and N,N-bis(1-methylethyl)ethanamine (0.00207 mol) were added andstirred at ambient temperature. After stirring for one hour, THF (10 ml)was added. The reaction mixture was heated to reflux for 64 hours andcooled to RT. The reaction mixture was diluted with EtOAc and treatedwith cold 1 M NaOH. The aqueous phase was extracted with EtOAc whilemaintaining the pH >10 with the addition of solid NaOH. The combinedorganic phases were dried over MgSO₄ and concentrated to afford 0.75 gyellow powder. The residue was crystallized from CH₃CN, filtered off anddried, yielding 0.64 g (90.7%) of4-[[4-[(2,4,6-trimethylphenyl)thio]-1,3,5-triazin-2-yl]amino]benzonitrile(compound 3).

Table 1 lists the compounds of formula (I′) which were preparedaccording to one of the above examples.

TABLE 1

Comp. Ex. No. No. X R^(a) R^(b) R^(c) Physical Data 1 B1a —NH— CH₃ CH₃CH₃ mp. 248–249° C. 2 B2a —O— CH₃ CH₃ CH₃ mp. 220–221° C. 3 B2a —O— CH₃Br Cl mp. 221–222° C. 4 B3 —S CH₃ CH₃ CH₃ mp. 256–257° C. 5 B2a —O— BrCH₃ Br mp. 255–257° C. 6 B1a —NH— Br CH₃ Br mp. 285–286° C. 7 B1a —NH—CH₃ Br CH₃ mp. 248–249° C. 8 B1b —NH— Br CH(CH₃)₂ Br mp. 245–247° C. 9B1c —NH CH₃ C(CH₃)₃ CH₃ mp. 249–250° C. 10 B1c —NH CH₃ CN CH₃ mp.252–254° C. 11 B2b —O— CH₃ CN CH₃ mp. 248–250° C.C. Pharmacological Example

EXAMPLE C.1

A rapid, sensitive and automated assay procedure was used for the invitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line,MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, 36,445–451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via the insitu reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was definedas the concentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:${\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu}{expressed}\mspace{14mu}{in}\mspace{14mu}\%},$whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (IC₅₀ inμM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). The compounds of formula (I′) were shown to inhibit HIV-1effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 3hereinbelow.

TABLE 2 Co. No. IC₅₀ (μM) CC₅₀ (μM) SI 1 0.0004 9.1 22722 20.0006 >100 >166666 3 0.0011 56.2 53536 4 0.0022 >100 >46511 5 0.001610.1 6452 6 0.0005 1.0 1901 7 0.0007 27.8 39722

1. A compound of formula

or a N-oxide, a pharmaceutically acceptable salt, or a stereochemicallyisomeric form thereof, wherein -b¹=b²-C(R^(2a))=b³-b⁴=represents abivalent radical of formula —CH═CH—C(R^(2a))═CH—CH═ (b-1);—N═CH—C(R^(2a))═CH—CH═ (b-2); —CH═N—C(R^(2a))═CH—CH═ (b-3);—N═CH—C(R^(2a))═N—CH═ (b-4); —N═CH—C(R^(2a))═CH—N═ (b-5);—CH═N—C(R^(2a))═N—CH═ (b-6); or —N═N—C(R^(2a))═CH—CH═ (b-7);

q is 0, 1, 2, 3 or 4; R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl,C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,C₁₋₆alkylcarbonyl, or C₁₋₆alkyloxycarbonyl; R^(2a) is cyano;aminocarbonyl; mono- or di(methyl)aminocarbonyl; C₁₋₆alkyl substitutedwith cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl;C₂₋₆alkenyl substituted with cyano; or C₂₋₆alkynyl substituted withcyano; each R² independently is hydroxy, halo, C₁₋₆alkyl optionallysubstituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyloptionally substituted with one or more halogen atoms or cyano,C₂₋₆alkynyl optionally substituted with one or more halogen atoms orcyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy,polyhalomethylthio, —S(═O)_(p)R⁴, —NH—S(═O)_(p)R⁴, —C(═O)R⁴, —NHC(═O)H,—C(═O)NHNH₂, —NHC(═O)R⁴, —C(═NH)R⁴ or a radical of formula

wherein each A independently is N, CH or CR⁴; B is NH, O, S or NR⁴; p is1 or 2; and R⁴ is methyl, amino, mono- or dimethylamino orpolyhalomethyl; L is C₄₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, orC₃₋₇cycloalkyl, whereby each of said aliphatic groups is optionallysubstituted with one or two substituents independently selected from (i)C₃₋₇cycloalkyl, (ii) indolyl or isoindolyl, each optionally substitutedwith one, two, three or four substituents each independently selectedfrom halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,nitro, amino, polyhalomethyl, polyhalomethyloxy or C₁₋₆alkylcarbonyl,(iii) phenyl, pyridinyl, pyrimidinyl pyrazinyl or pyridazinyl, whereineach of said aromatic rings is optionally substituted with one, two,three, four or five substituents each independently selected from thesubstituents defined in R²; or L is —X—R³ wherein R³ is phenyl,pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of saidaromatic rings is optionally substituted with two, three, four or fivesubstituents each independently selected from the substituents definedin R²; and X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—,—S(═O)— or —S(═O)₂—; aryl is phenyl or phenyl substituted with one, two,three, four or five substituents each independently selected from halo,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkylor polyhaloC₁₋₆alkyloxy.
 2. A compound as claimed in claim 1 wherein Lis —X—R³, —X— is —O— or —NH— and R³ is phenyl substituted with two orthree substituents each independently selected from chloro, bromo, cyanoor methyl.
 3. A compound as claimed in claim 1 wherein R^(2a) is cyano,aminocarbonyl, mono- or di(methyl)aminocarbonyl, C₁₋₆alkyl substitutedwith cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl.
 4. Amethod of treating a subject suffering from Human Immunodeficiency Virus(HIV) infection, comprising administering a therapeutically effectiveamount of a compound of claim 1 to said subject.
 5. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of compound as claimed in claim
 1. 6. Aprocess for preparing a pharmaceutical composition as claimed in claim 5comprising mixing a therapeutically effective amount of said compoundwith a pharmaceutically acceptable carrier.
 7. The combination of acompound as defined in claim 1 and another antiretroviral compound.
 8. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and as active ingredients (a) a compound as defined in claim 1,and (b) another antiretroviral compound.
 9. The method of claim 4further comprising administering a therapeutically effective amount ofanother antiretroviral compound to said subject.
 10. The method of claim9 wherein said compound and said another antiretroviral compound areadministered simultaneously, separately, or sequentially to saidsubject.